We recently isolated a mutant of the nebula gene, or the Drosophila ortholog of DSCR1 (Down syndrome critical region 1) gene, which is overexpressed in the brains of DS fetuses. DSCR1 can bind to and inhibit calcineurin, an important phosphatase associated with learning and memory. Given that DSCR1 is overexpressed in the DS fetal brain and calcineurin participates in the learning and memory pathway, we are interested in examining the role of DSCR1 overexpression in regulating learning and memory by using Drosophila as a simple model organism. The nebula protein shares 43% identity and 64% similarity in amino acid sequence with exon 1 of human DSCR1. We have shown that nebula is highly expressed in the brain cortex of the normal fly. Strikingly, Pavlovian olfactory learning and memory test revealed that nebula homozygous mutant has significantly reduced learning and a complete absence of long-term memory, but short-term memory remains intact. These results reveal that nebula is capable of inhibiting calcineurin and mediating learning and long-term memory. It still remains to be determined how overexpression of DSCR1, as in the case of DS, will affect learning and memory. Therefore we will undertake experiments aimed at understanding the biochemical and functional consequences of nebula overexpression, as well as finding ways to improve or repair the defective learning and memory that may result from overexpression. To study the effects of DSCR1 overexpression, transgenic flies overexpressing nebula are currently being generated by germ line transformation. Thus far, we have successfully obtained three different transgenic fly lines containing the nebula gene under UAS (upstream activation sequence) for GAL4 binding. To understand the physiological effect of nebula overexpression, we will use the Pavlovian olfactory learning and memory test.